Left Ventricular Remodeling Process Research Articles

Determinants of Left Ventricular Geometric Alterations and Related Clinical and Metabolic Factors in a General Population

Left ventricular (LV) remodeling has been shown to impart prognostic significance in previous studies. However, the underlying exact mechanisms involved and interactions between LV geometry alterations and age with other clinical and biochemical variables in general population have not been well established. A total of 406 consecutive subjects were enrolled in a health evaluation center-based population study (mean age, 51.5 ± 10.9 years; 42% women). Data including baseline characteristics, echocardiography, biochemistry and biomarkers were all collected and evaluated. Univariate and multivariate regression analysis was performed to test the relationship between relative wall thickness (RWT) and other variables. We also divided the subjects into older and younger groups, compared RWT between the two groups, and analyzed the distribution of LV geometry in these groups. The prevalence of diabetes and hypertension in our study population was relatively small (11.6% and 16.5%, respectively). The most common type of LV geometry in our study was normal (67.5%) and concentric remodeling (30.3%) compared with a relatively small proportion of concentric LV hypertrophy (1.5%) and eccentric hypertrophy (< 1%). Of all 406 subjects evaluated, age, uric acid, height, systolic blood pressure and serum insulin level were all independent factors associated with RWT in a multivariate regression model. In our study, we revealed that aging, together with baseline blood pressure and serum biochemistries, were associated with LV geometric alterations. These data suggest that the LV remodeling process actually involves dynamic and complex interactions with multiple metabolic factors in an unselected general population in Taiwan.

The effect of ageing on cardiac remodelling and hospitalization for heart failure after an inaugural anterior myocardial infarction

Following myocardial infarction (MI), both age and left ventricular (LV) remodelling are associated with an increased risk of adverse events. We tested the hypothesis that the increased incidence of heart failure following MI in elderly patients is associated with a greater propensity for LV remodelling. We monitored 266 patients with anterior MI. Echocardiographic studies were performed at hospital discharge, at 3 months, and at 1 year following hospitalization for MI. A clinical follow-up examination was performed after 3 years. Left ventricular remodelling was documented by an increase in LV end-diastolic volume after 1 year. Left ventricular end-diastolic and end-systolic volumes did not differ with age for all time points studied. Left ventricular remodelling was observed in 31, 26, 34, and 34% of patients <48, 48-57, 58-71, and >71 years of age, respectively. The 3 year heart-failure hospitalization rates were 1.9, 1.5, 11.0, and 20.3% for patients <48, 48-57, 58-71, and >71 years of age, respectively. Hospitalization for heart failure was more frequent in older patients. We found that age was a major determinant of subsequent re-hospitalization for heart failure. However, we found no significant association between age and the LV remodelling process.

Effects of Oral Amino Acid Supplements on Cardiac Function and Remodeling in Patients with Type 2 Diabetes with Mild-to-Moderate Left Ventricular Dysfunction

The aim of this study was to evaluate the effects of an oral special mixture of amino acid (AA) supplements alongside angiotensin-converting enzyme (ACE) inhibitor therapy on left ventricular (LV) function and symptoms in patients with type 2 diabetes mellitus with mild-to-moderate LV dysfunction. It is established that the remodeling process is associated with late onset of heart failure and decreased survival. ACE inhibitor therapy reduces progressive increases in LV dimensions and significantly improves the clinical course of a broad spectrum of patients with LV dysfunction. Moreover, AA supplements prevent myocardial dysfunction caused by exercise in patients with type 2 diabetes. In addition to ACE inhibitor therapy, patients with diabetes were randomly assigned to receive AA supplements or placebo. LV function and dimensions were assessed with quantitative echocardiographic tests at intake into the study and after 6 months of follow-up. In patients with type 2 diabetes, LV end-diastolic index was reduced significantly during the 6-month period of AA consumption (89 +/- 9 mL/m2 vs 76 +/- 8 mL/m2; p <0.01), and LV ejection fraction (LVEF) improved (0.46 +/- 0.07 vs 0.52 +/- 0.05; p <0.001). No significant changes in LVEF or LV end-diastolic index occurred in the placebo group. These findings suggest that AA supplementation, together with ACE-inhibitor therapy, may have a beneficial effect on the LV remodeling process in patients with type 2 diabetes with mild-to-moderate LV dysfunction.

Telomere Gap Between Granulocytes and Lymphocytes Is a Determinant for Hematopoetic Progenitor Cell Impairment in Patients With Previous Myocardial Infarction

We have previously demonstrated that ischemic cardiomyopathy is associated with selective impairment of progenitor cell function in the bone marrow and in the peripheral blood, which may contribute to an unfavorable left ventricular remodeling process. With this study, we intended to identify the influence of telomere length on bone marrow functionality in 50 patients with coronary artery disease (CAD) and previous myocardial infarction. Mean telomere length (mTL) was measured simultaneously in peripheral blood leukocytes and mononuclear bone marrow cells (BMC), using the flow-FISH method. Telomere erosion already occurred at the bone marrow level, whereby age (39 bp/yr, P=0.025) and the number of affected vessels (434 bp/vessel, P=0.029) were the only independent predictors. Lymphocytes demonstrated significant TL shortening between BMCs and peripheral blood in CAD patients (-1011+/-897 bp) as opposed to an increase in a young control group (+235+/-459 bp, P<0.001). SDF- and VEGF-specific migration of BMCs correlated with mTL of lymphocytes (r=0.42, P<0.001) and was significantly reduced in CAD patients. Finally, the telomere length difference between granulocytes and lymphocytes was the most determinant for telomere-associated bone marrow impairment (P<0.001). In patients with CAD, telomere shortening of BMCs is dependent on both age and the extent of CAD and correlates with bone marrow cell functionality.

Plasma MMP-2, MMP-9 and N-BNP in Long-Term Survivors Following Complicated Myocardial Infarction: Relation to Cardiac Magnetic Resonance Imaging Measures of Left Ventricular Structure and Function

Background Altered activity of the matrix metalloproteinases (MMP-2 and -9), has been implicated in the left ventricular (LV) remodeling process occurring after myocardial infarction (MI). In the acute phase, a relation between plasma MMP-9 levels and parameters of LV dysfunction has been demonstrated. The relationship in long-term survivors has not been investigated. We studied the relationships of these biochemical markers, and N-terminal pro-B-type natriuretic peptide (N-BNP), with measures of long-term LV remodeling. Methods and Results Plasma levels of N-BNP, MMP-2, and MMP-9 were measured at randomization, 1 month, 1 year, and >4 years after complicated AMI. Contrast-enhanced cardiac magnetic resonance (CMR) was performed at 4.4 (±0.4) years in 52 clinically stable long-term survivors of the index AMI. We assessed the relationships of plasma N-BNP, MMP-2, and MMP-9 with myocardial scarring, and measures of long-term LV remodeling. Compared with a reference population, N-BNP and MMP-9 levels were increased at all time points from the acute phase until >4 years after MI. Plasma N-BNP and MMP-9 correlated only in the subacute phase (randomization, mean 3.3 days after MI) days after acute MI ( r = 0.38, P = .006). At CMR assessment ≥4 years, log MMP-9 level was inversely related to LV ejection fraction ( P = .002) and nonscarred myocardial mass ( P = .008). This relationship was independent of MMP-2. Log N-BNP was related to end diastolic volume index ( P = .0002). There was no correlation between log MMP-9 and LV volumes. Conclusion There is a time-dependent relationship between plasma N-BNP and MMP-9 levels, these peptides correlating only in the acute phase after MI. In long-term follow-up, plasma MMP-9 and N-BNP levels were related to different parameters of LV remodeling. These findings suggest that in long-term survivors of complicated MI, different mechanisms modulate plasma levels of MMP-9 and N-BNP.

Abstract 1706: Elevation of Pericardial Fluid Active Matrix Metalloproteinase-9 (MMP-9) Level Is Closely Associated With Left Ventricular Remodeling

Background: The development of congestive heart failure (CHF) is associated with left ventricular (LV) remodeling. However, fundamental mechanisms that contribute to this remodeling process remain unclear. The matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) have been demonstrated to play a significant role in tissue remodeling through a number of pathological processes. Objectives: The purpose of this study was to investigate whether MMPs and TIMPs represent autocrine/paracrine factors and are accumulated in pericardial fluid. We previously reported that active MMP-2 levels in pericardial fluid served as more sensitive and accurate indicators of LV remodeling than did active MMP-2 levels in plasma. Methods: We measured the concentrations of the enzyme (active MMP-9) in both plasma and pericardial fluid in 20 patients during coronary artery bypass graft surgery. Results: The active MMP-9 level was significantly higher in pericardial fluid than in plasma (4.68 ± 1.17 vs. 2.58 ± 0.29 ng/ml, p&lt;0.0001). Interestingly, the pericardial fluid levels of active MMP-9 were significantly higher in patients with impaired LV function than in those with normal LV function (5.25 ± 0.57 vs. 2.96 ± 0.65 ng/ml, p&lt;0.0001). Pericardial fluid active MMP-9 levels had closer relations with LVEDVI (r=0.459, p=0.047) and LVESVI (r=0.490, p=0.0321) than did plasma active MMP-9 levels (LVEDVI: r=0.065, p=NS; LVESVI: r=0.254, p=NS). Active MMP-9 levels in pericardial fluid but not in plasma inversely correlated with LV ejection fraction (r=−0.626, p=0.0033). Conclusions: Active MMP-9 levels in pericardial fluid serve as more sensitive and accurate indicators of LV remodeling than did active MMP-9 levels in plasma. Thus, active form of MMP-9 may be also secreted from the heart into the pericardial space with the progression of CHF, and it may have a pathophysiologic role in LV remodeling process as an autocrine/paracrine factor.

Selective Functional Exhaustion of Hematopoietic Progenitor Cells in the Bone Marrow of Patients With Postinfarction Heart Failure

This study investigated whether reduced levels of circulating endothelial progenitors cells (EPCs) in chronic heart failure (CHF) are secondary to an exhaustion of hematopoietic stem cells (HSCs) in the bone marrow or to reduced mobilization. Circulating EPCs presumably originate from bone marrow-derived HSC. Persistent mobilization of EPCs was shown to be associated with favorable left ventricular infarct remodeling processes. We assessed the number and functional capacity of EPCs in 17 healthy controls, 25 patients with ischemic cardiomyopathy (ICM), and 20 patients with dilated cardiomyopathy (DCM). To document an impairment of HSC function in the bone marrow, the colony-forming unit capacity of bone marrow-derived mononuclear cells and the number of CD34+ HSCs were examined in 6 healthy volunteers, 94 ICM patients, and 25 DCM patients. The number of EPCs was reduced in CHF, irrespective of its etiology. In contrast, the migratory capacity was selectively impaired in EPCs of ICM patients (4.8 +/- 4.0 migrated cells; DCM 9.7 +/- 5.8; p = 0.02). On multivariate analysis, ICM, advanced New York Heart Association functional class, and CHF were independent predictors of functional EPC impairment. The number of bone marrow-derived CD34+ cells did not differ between the CHF populations. However, colony-forming units (CFUs) were selectively reduced in ICM patients (54.4 +/- 24.6; DCM 68.1 +/- 26.9; p < 0.02). Ischemic cardiomyopathy was the only independent predictor of impaired CFU capacity. Impaired CFU capacity was associated with reduced matrix metalloproteinase-9 activity in the bone marrow plasma. Ischemic cardiomyopathy is associated with selective impairment of progenitor cell function in the bone marrow and in the peripheral blood, which may contribute to an unfavorable left ventricular (LV) remodeling process.

Angiotensin II, oxidative stress, and extracellular matrix degradation during transition to LV failure in rats with hypertension

Angiotensin II (Ang-II) plays pivotal roles in the progression of left ventricular (LV) remodeling in diseased hearts; it remains to be elucidated how Ang-II links to degradation of the extracellular matrix (ECM). Using hypertensive Dahl salt-sensitive rats that show the distinctive transition from concentric LV hypertrophy to LV remodeling, we chronically treated them with an angiotensin type-1 receptor blocker (telmisartan 5 mg/kg/day, ARB group) or vehicle (0.5% CMC, CHF group). During the process of LV remodeling, we assessed, (1) in-vivo LV shape and function; (2) animal survival; (3) amounts of ECM in LV using a scanning electron microscope (SEM); (4) mRNA (by real time RT-PCR) and protein (by immunoblotting) levels in LV of NADPH oxidase, glutathione peroxidase-1 (GPX-1), and matrix metalloproteinase (MMP)-2, -9, and -13; (5) immunohistochemical staining of myocardial 4-hydroxy-2-nonenal and 8-hydroxy-2′-deoxyguanosine; (6) nuclear factor kappa-B (NFκB) protein levels in the nuclear extract; and (7) endogenous activities of MMP-2 and -9 by an antibody capture method. Compared with CHF, ARB group showed an improvement of survival and preserved LV shape and function, and ECM density in SEM that was accompanied by decreases in oxidative stress-mediated protein degenerations, activities of GPX-1, NADPH oxidase, NFκB, and MMP-2, -9, and -13. Local activation of Ang-II in hypertrophic LV triggers MMP-mediated ECM degradation, namely LV remodeling, at least in part, through NADPH oxidase-induced oxidative stress and the subsequent NFκB activation.

Clinical outcomes of surgery of mitral valve regurgitation and coronary artery bypass grafting

The impact of etiology of associated mitral valve regurgitation and a valve procedure on operative and long-term outcomes after coronary bypass grafting surgery is yet to be clearly defined. Results of combined coronary artery bypass grafting and valve procedures for mitral valve regurgitation were retrospectively analyzed in 468 patients. The regurgitation was of ischemic in 45%, degenerative in 55% and 78% valve repairs, 22% valve replacements were performed. Severe coronary artery disease, acute myocardial infarction, low ejection fraction, ischemic mitral regurgitation, advanced heart failure symptoms, failure to use internal mammary artery, valve replacement surgery, and emergency operations are predictors of operative mortality. The 5-year survivals for propensity-matched patients of ischemic and degenerative disease were similar (66%), but 67% vs. 83%, respectively, for unmatched patients. Low ejection fraction (<35%), advanced age (>67 years), valve replacement surgery, residual mitral regurgitation, and severe coronary artery disease were predictors of poor long-term survival. Left ventricular remodeling processes, optimal valve procedure without residual mitral regurgitation and left ventricular function are important determinants of long-term outcome than the etiology of valve regurgitation.

The effect of resistance training on left ventricular function and structure of patients with chronic heart failure

Introduction Resistance training (RT) has been shown to improve chronic heart failure (CHF) patients' functional ability and quality of life. Despite these benefits RT has not always been recommend as a form of exercise principally because of a concern for acceleration of the left ventricular (LV) remodeling process. This study investigated the effects of 8 weeks RT on the LV structure and function of patients with CHF. Method Fifteen men who suffered from CHF were divided into either a RT program or non-training control group. Before and after 8 weeks of training patients underwent resting echocardiography to assess their end-diastolic and end-systolic dimensions (EDD and ESD, respectively), ejection fraction (EF), fractional shortening (FS) and stroke volume (SV). Results A repeated measured ANOVA showed that 8 weeks of RT had no significant effect on the LV measurements (group×time, p>0.05). Post training comparison, however, revealed that the EF and FS of the training group was significantly higher than in the control group (40.9±10.5% vs. 30.3±4.6%, p=0.029 and 25.0±7.0% vs. 17.4±3.1%, p=0.020 respectively). Conclusion RT is a suitable method of training for CHF patients since it does not cause a reduction of LV contractility function or enhance myocardial deterioration as measured by EF and FS.

Molecular Beacons Illuminate Subcellular Events

Building on decades of technological advances and imaging experience, during which noninvasive imaging of cardiac structure and function, myocardial perfusion and viability, and noncoronary vascular pathology have become intimately entwined in routine clinical practice, advanced imaging techniques are now poised to deliver noninvasive coronary arteriograms and to delineate the coronary artery wall in exquisite detail. At the same time that these highly promising methods for anatomic imaging at the macroscopic level are creating great excitement among physicians, their patients, and the public, a quieter imaging revolution is underway with steady progress in detecting and tracking fundamental biological processes at the cellular and subcellular levels. In the era of genomic research, molecular biology, and stem cell therapies, these methods have great potential to accelerate understanding of basic pathophysiological processes in animals and humans and to develop new tools for early diagnosis and drug development. Cardiovascular molecular imaging is taking hold. See p 1800 Molecular imaging is the science of visually representing, characterizing, and quantifying cellular/subcellular biological processes in intact organisms. These processes include gene expression, protein–protein interaction, signal transduction, cellular metabolism, and both intracellular and intercellular trafficking. Molecular imaging has the potential to quantify these events, to monitor multiple events simultaneously, to localize these events in 3 dimensions, and to monitor these events serially. Thus, biological processes can be identified and studied in time and space, providing “4-dimensional” information. The emergence of molecular imaging has coincided with and has been made possible by the enormous progress in molecular biology, cell biology, and transgenic animal models, as well as the development of imaging probes that are specific, reproducible, and quantifiable.1 Molecular imaging was once the sole domain of nuclear medicine, with tracers developed for both positron emission tomography (PET) and single photon emission computed tomography (SPECT). Examples include antimyosin antibodies for …

Early, selective growth hormone administration may ameliorate left ventricular remodeling after myocardial infarction

Left ventricular (LV) remodeling after myocardial infarction (MI) may lead to congestive heart failure, disability and death. It consists of expansion of the infarct zone and dilatation of the non-infarcted myocardium, causing shape distortion and ventricular enlargement. Experimental studies have shown that treatment with growth hormone (GH) stimulates cardiac repair, resulting in increased infarct zone collagen scar formation and possibly enhanced proteinosynthesis. These actions may ameliorate the process of LV remodeling. We hypothesize that these beneficial effects may be more prominent, if GH is delivered selectively in the infarct area, during the early phase of acute MI. Experimental and clinical studies are necessary to validate this hypothesis.

Ventricular remodeling in heart failure and the effect of β-blockade

Left ventricular (LV) remodeling has an important role in the progression of cardiovascular disease. An understanding of the process of LV remodeling has led to greater knowledge of the pathophysiology of heart failure. Drug therapies that slow or reverse the remodeling process seem to have favorable natural history effects in short-term and long-term therapy. Angiotensin-converting enzyme (ACE) inhibitors have been associated with a significant reduction in mortality, and the effect of β-blockers on the remodeling process has now been studied across much of the spectrum of severity in patients with heart failure. β-Blockade seems to add favorable and independent effects on the post–myocardial infarction remodeling process over and above those of ACE inhibitors. A combination of both drugs shows the greatest reduction in mortality (ie, the most favorable reverse remodeling). Differences in their effect on remodeling have been recently shown among the β-blockers. Several studies and a meta-analysis suggest that carvedilol may be more favorable to outcome, having the most effect on LV remodeling.

Influence of Perindopril on Left Ventricular Remodeling in Essential and Secondary Hypertension

Background: To evaluate the relation between the left ventricular hypertrophy (LVH) regression and changes of LV diastolic function under the influence of perindopril in patients (pts) with hypertension. Methods: Fifty-two pts with essential hypertension (EH) and 36- with secondary arterial hypertension (SAH) of renal genesis with II-III grade hypertension, LVH and abnormal mitral flow pattern have been studied to assess effect of perindopril (up to 4 mg/day) on left ventricular remodeling. Each subject was underwent two-dimensional and Doppler-echocardiography. LV mass index (LVMI), LV end-diastolic diameter (EDD), septal and posterior wall thickness (SWT, PWT) were evaluated, the following parameters of LV diastolic function were assessed by Doppler echocardiographic analysis of the diastolic transmitral flow: the maximal early- (E) and late–(A) velocity of diastolic filling; the E/A ratio, the deceleration time (DT) and the isovolumetric relaxation time (IVRT). Examination was performed at baseline and after 48 weeks of treatment with perindopril. Results: In pts with EH systolic BP (SBP) was reduced on average from 190±22 to 136±10 mm Hg., diastolic BP (DBP) from 113±11.2 to 84±12 mm Hg. In pts with SAH there was detected reduction of SBP and DBP from 206±24 to 142±10 mm Hg and 115±11.1 to 86±11 mm Hg, respectively. LVMI was reduced by 14.2 % in EH and by 13.0 % in SAH (p<0.01 for both). PWT decreased by 12.2 % in EH (p<0.01) and by 7.4 % in SAH (p<0.05), SWT by 6 % (p<0.05) and 14.6 % (p<0.001), respectively. Perindopril treatment produced shortening of IVRT (102.6±4.24 vs 146.8±7.90 ms in EH, and 102.0±2.92 vs 154.0±6.00 ms in SAH, p<0.01 for both), DT (180.0±7.42 vs. 230.0±12.9 ms in EH, p<0.01 and 184.0±7.86 vs. 204.6±9.60 ms in SAH, p<0.05), E (68.8±6.4 vs. 50.0±10.0 cm/s in EH and 56.0±10.3 vs. 46.0±10.0 cm/s in SAH, p<0.05 for both), increased E/A ratio (from 0.82±0.10 to 0.96±0.12 in EH and from 0.70±0.04 to 0.86±0.16 in SAH, p<0.05 for both) and had trend toward decreasing A (68.8±10.0 vs. 86.2±12.0 cm/s in EH and 70.0±10.4 vs. 82.5±12.3 in SAH cm/s, p = NS for both). At the end of follow up normal mitral flow pattern was detected in 46.8 % pts with EH and 39.2 % pts with SAH. Increased in E/A was related to reduction of SWT in pts with SAH (r = 0.69, p<0.05), while in EH at the account of diminution of the LV EDD (r = 0.50, p<0.05). Conclusion: Perindopril treatment has significantly ptoduced the attenuation of the left ventricular remodeling process in pts with EH and SAH. Diastolic function improvement in pts with SAH was related to the reduction of SWT, while in EH -to the reduction of the left ventricular cavity size.

730 Effect of the rate of D dimer level increase on the process of left ventricular myocardial remodeling

730 Effect of the rate of D dimer level increase on the process of left ventricular myocardial remodeling

Relation between left ventricular remodeling and clinical outcomes in heart failure patients with left ventricular systolic dysfunction

Background: A major advance in understanding the pathophysiology of the heart failure syndrome has been an understanding of the process of left ventricular (LV) remodeling. After any insult to the left ventricle resulting in diminished systolic performance and stroke volume, a series of histopathologic changes in the myocardium and structural changes in the LV chamber occurs over time. Methods and Results: Early work on understanding this process of LV remodeling emerged from the studies of Pfeffer and colleagues, who used a rat model of myocardial infarction (MI). Compared to those with smaller MIs, rats with larger induced MIs underwent a substantially greater degree of chamber remodeling over time, and importantly, these structural changes were associated with significantly higher morality. These studies established for the first time the relation between the structural changes now widely known as LV remodeling and a natural history outcome in the setting of LV systolic dysfunction. Subsequently, these investigators demonstrated that angiotensin-converting enzyme (ACE) inhibition with captopril, when initiated soon after the induced MI, attenuated the remodeling process. Also observed was an improvement in survival among rats in whom the remodeling process has been attenuated. These important data paved the way for human studies that have subsequently provided substantial evidence to support two important concepts: (1) that LV remodeling is related to clinical outcomes that represent the natural history of the heart failure syndrome such as mortality and surrogate markers of the progression of heart failure, and (2) that therapeutic interventions in humans that slow or reverse the process of LV remodeling, such as ACE inhibitors and β-blockers, appear to have a favorable effect on that natural history. Conclusions: This review will examine the issue of the relation between LV remodeling and clinical outcomes in the human heart failure syndrome from several interrelated aspects: (1) the relation between LV volume at one time point and subsequent oucome, (2) the relation between changes in LV volumes over time (LV remodeling) and clinical outcomes, and (3) the relation between the effect of medical therapeutic interventions on the LV remodeling process and the effect of those same medical interventions on natural history outcomes in human heart failure.

Tumor necrosis factor–induced signal transduction and left ventricular remodeling

Recent studies have identified the importance of biologically active molecules such as neurohormones in disease progression in heart failure. More recently, it has become apparent that in addition to neurohormones another portfolio of biologically active molecules termed cytokines are also expressed in the setting of heart failure. This article will review the role of tumor necrosis factor–induced signal transduction and the process of left ventricular remodeling.

Ventricular remodeling in heart failure

This review briefly highlights the major mechanisms of left ventricular (LV) remodeling following myocardial infarction in heart failure and presents novel strategies to limit infarct size and retard the progression of LV remodeling. This is important since interventions that have been shown to improve mortality in patients with heart failure such as angiotensin converting enzyme inhibitor and β-blockers had a favorable impact on the LV remodeling process. Although several other animal models of heart failure are available, we chose the rat infarct model because of its accurate reflection of human pathophysiology. It is clear from this review that the understanding of the mechanisms responsible for the regression of ventricular remodeling is still unclear. Further investigations in this area will certainly lead to the development of new therapy for heart failure.

Clinical profile of chronic heart failure in elderly women.

The pathogenesis, clinical course, and treatment of chronic heart failure (HF) are different in elderly women from those of patients recruited in the landmark trials of chronic HF. Patients included in these landmark trials were predominantly men whose age was 10-15 years younger than the average age of patients with chronic HF in the United States. Diastolic dysfunction resulting in impaired left ventricular (LV) filling is the preponderant LV functional alteration that leads to chronic HF in elderly women. Gender differences in the LV remodeling process that accompanies chronic cardiac pressure are likely to be responsible for the preponderance of LV diastolic dysfunction over systolic dysfunction in elderly women. In response to chronic pressure overload, the LV wall becomes thicker in women than in men. Consequently, in response to chronic pressure overload, women are able to normalize LV wall stress and preserve LV systolic function to a greater extent than men. However, impaired LV filling is an undesirable consequence of the greater increase in LV wall thickness in women. Thus, clinical observations and therapeutic guidelines derived from data collected in the landmark trials of chronic HF may not apply to elderly women with chronic HF. In view of the lack of evidence-based information needed to guide the management of elderly women with chronic HF, special attention should be given to include a substantial number of elderly women in future therapeutic trials recruiting patients with chronic HF.

Matrix metalloproteinases: regulation and dysregulation in the failing heart.

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes responsible for myocardial extracellular protein degradation. Several MMP species identified within the human myocardium may be dysregulated in congestive heart failure (CHF). For example, MMPs that are expressed at very low levels in normal myocardium, such as collagenase-3 (MMP-13) and the membrane-type-1 MMPs, are substantially upregulated in CHF. However, MMP species are not uniformly increased in patients with end-stage CHF, suggesting that a specific portfolio of MMPs are expressed in the failing myocardium. With the use of animal models of CHF, a mechanistic relationship has been demonstrated with respect to myocardial MMP expression and the left ventricular (LV) remodeling process. The tissue inhibitors of the MMPs (TIMPs) are locally synthesized proteins that bind to active MMPs and thereby regulate net proteolytic activity. However, there does not appear to be a concomitant increase in myocardial TIMPs during the LV remodeling process and progression to CHF. This disparity between MMP and TIMP levels favors a persistent MMP activation state within the myocardium and likely contributes to the LV remodeling process in the setting of developing CHF. The elucidation of upstream signaling mechanisms that contribute to the selective induction of MMP species within the myocardium as well as strategies to normalize the balance between MMPs and TIMPs may yield some therapeutic strategies by which to control myocardial extracellular remodeling and thereby slow the progression of the CHF process.